NONCANATM

DNA damage response: ATMIN regulated non-canonical ATM activation

Coordinatore	CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH    more  Organization address address: Dr. Ignaz Seipel-Platz 2 city: WIEN postcode: 1010 contact info Titolo: Ms. Nome: Angelika Cognome: Eisner Email: send email Telefono: +43 1 40160 70028
Nazionalità Coordinatore	Austria [AT]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2012-CIG
Funding Scheme	MC-CIG
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-09-01   -   2016-08-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH  Organization address address: Dr. Ignaz Seipel-Platz 2 city: WIEN postcode: 1010 contact info Titolo: Ms. Nome: Angelika Cognome: Eisner Email: send email Telefono: +43 1 40160 70028	AT (WIEN)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'The checkpoint kinase ATM (Ataxia Telangiectasia Mutated) transduces genomic stress signals to halt cell cycle progression and promote DNA repair in response to DNA damage. ATMIN (for ATM INteractor) is a cofactor for ATM that shares functional homologies with another cofactor, NBS1. Whereas NBS1 is required for ATM function after induction of double-stand breaks (DSBs), ATMIN is essential for ATM signaling triggered by agents that induce ‘chromatin changes’ (including chloroquine and osmotic stress). However, the significance of this non-canonical mode of ATM signaling has been unclear. My recent work has shown that the ATMIN/ATM signaling pathway is crucial for the function of the ATM kinase, and hence the maintenance of genomic integrity and tumour suppression. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN in B cells. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. As a consequence, ATMIN deficiency led to impaired class switch recombination, and subsequently ATMIN-mutant mice developed B cell lymphomas. Thus, somewhat surprisingly given the large body of evidence supporting a role for NBS1 in ATM activation, ablation of ATMIN-dependent ATM activation leads to a severe defect in ATM function. Thus this data strongly argues for the existence of a second independent mode of ATM activation that contributes to ATM function. The molecular trigger (which can be mimicked by osmotic stress) and the components of this second ATMIN-dependent arm of the ATM pathway are unknown, but my data clearly show that it is physiologically relevant. It is worth noting that while a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, very little is known about non-canonical ATM signaling. The experiments outlined in my research plan have the aim to understand the molecular basis of this pathway.'